Dementia, with its most prevalent subforms Alzheimer's disease (AD), dementia with Lewy bodies (DLB), and vascular dementia, is a very substantial medical and societal problem. The emergence of many drugs and drug candidates that interfere with the disease mechanism of specific types of dementia makes it crucial to distinguish early between the various forms. Useful diagnostic tools will make it possible to direct patients to the most appropriate drug regimen, to avoid exposure to potentially harmful drugs, and to monitor the efficacy of disease-modifying drugs. Brain imaging techniques provide a non-invasive tool for differential diagnosis and monitoring of disease progression of dementia. We and others have been developing radiopharmaceuticals that allow detection of A amyloid deposits typical for AD. Our efforts have focused on 18F-labeled compounds for PET imaging, with the goal that the imaging diagnostics can be made widely available at minimal costs. We now propose the clinical development of a new radioligand for the differential diagnosis of DLB from AD as well as the monitoring of DLB disease progression. 18F-AV-133 is a highly selective ligand for the vesicular monoamine transporter VMAT2, believed to be the best marker for the functional integrity of dopaminergic neurons which are known to degenerate in DLB. Our proposal tests that hypothesis that imaging of VMAT2 provides a useful biomarker for dopaminergic neuron degeneration, which can be synergistically combined with amyloid plaque imaging to generate a powerful diagnostic work up for classification of dementia patients. We propose to conduct two clinical studies to establish safety and proof-of-concept for 18F-AV-133 as a diagnostic imaging agent for DLB. PUBLIC HEALTH RELEVANCE: Successful completion of the proposed phase I studies will provide a key step towards the provision of diagnostic tools for the clinical diagnosis and monitoring of disease progression of dementia with Lewy bodies (DLB), Alzheimer's disease (AD) and dementias in general. The studies will identify a diagnostic tool to allow the physicians to direct patients towards the most appropriate drug regimen and prevent that the patients are exposed to potentially harmful drugs. Furthermore, the resulting diagnostic tools will help significantly in the development of disease-modifying drugs, by making it possible to monitor treatment efficacy at the molecular level in vivo. Such a diagnostic tool will represent a significant technological and medical benefit to society. [unreadable] [unreadable] [unreadable]